2. Academic Validation
  3. Discovery of CW-3308 as a Potent, Selective, and Orally Efficacious PROTAC Degrader of BRD9

Discovery of CW-3308 as a Potent, Selective, and Orally Efficacious PROTAC Degrader of BRD9

  • J Med Chem. 2024 Aug 22;67(16):14125-14154. doi: 10.1021/acs.jmedchem.4c00971.
Changwei Wang 1,  Mi Wang 1,  Yu Wang 1,  Rohan Kalyan Rej 1,  Angelo Aguilar 1,  Tianfeng Xu 1,  Longchuan Bai 1,  Jelena Tošović 1,  Donna McEachern 1,  Qiuxia Li 2,  Farzad Sarkari 2,  Bo Wen 2 3,  Duxin Sun 2 3,  Shaomeng Wang 1 4 5 3
Affiliations

Affiliations

  • 1 Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 2 Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 3 Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 4 Department of Pharmacology, Medical School, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 5 Department of Medicinal Chemistry, College of Pharmacy,, University of Michigan, Ann Arbor, Michigan 48109, United States.
PMID: 39132814 DOI: 10.1021/acs.jmedchem.4c00971
Abstract

The bromodomain-containing protein BRD9 has emerged as an attractive therapeutic target. In the present study, we successfully identified a number of highly potent BRD9 degraders by using two different Cereblon ligands developed in our laboratory. Further optimization led to the discovery of CW-3308 as a potent, selective, and orally bioavailable BRD9 Degrader. It displayed degradation potency (DC50) < 10 nM and efficiency (Dmax) > 90% against BRD9 in the G401 rhabdoid tumor and HS-SY-II synovial sarcoma cell lines and had a high degradation selectivity over BRD7 and BRD4 proteins. CW-3308 achieved 91% of oral bioavailability in mice. A single oral dose efficiently reduced the BRD9 protein by >90% in the synovial sarcoma HS-SY-II xenograft tumor tissue. Oral administration effectively inhibited HS-SY-II xenograft tumor growth in mice. CW-3308 is a promising lead compound for further optimization and extensive evaluation for the treatment of synovial sarcoma, rhabdoid tumor, and other BRD9-dependent human diseases.

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